Cardiotrophin-like cytokine (CLC), identified in silico by sequence homology analysis, belongs to the IL-6 family of cytokines. Although possessing a putative signal peptide, the cytokine appears to be retained within the cell unless coexpressed with the solubletype I cytokine receptor cytokine-like factor (CLF). CLF and CLC associate to form a stable secreted complex in a manner similar to the formation of the IL-12 heterodimer. The CLF/CLC composite cytokine acts on cells expressing the tripartite ciliary neurotropic factor (CNTF) receptor complex and therefore represents the second known ligand for thisparticular receptor. The contrasting phenotype of mice deficient in either CNTF or the ligand-binding nonsignaling ♂ chain of the CNTF receptor complex, CNTFR♂, has suggested for some time the existence of a second, developmentally important ligand for the CNTF receptor. The fact that CLF-deficient mice have a phenotype similar to those deficientin CNTFR♂ goes a long way towards demonstrating this ligand to be CLF/CLC. Due to its well-established neuroprotective effects, CNTF has shown promise in certain clinical trials for the treatment of neurodegenerative disorders. As both CNTF and CLF/CLC have overlapping biological properties, it would be of great interest to examine the effects ofthe CLF/CLC complex in similar studies.